Stable Aqueous Suspension

ABSTRACT

An aqueous suspension of a hydrophobic nutrient is disclosed. In particular, the nutrient, in ester form, is combined with a selected dispersion aid and a dispersion agent(s), and then dispersed in an aqueous medium to form the suspension.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a stable aqueous suspension comprising anutrient, as well as to a method of rendering a normally hydrophobicnutritional compound or ingredient dispersible in water or in an aqueoussystem.

2. Description of the Related Art

Nutritional compounds, i.e. nutritional supplements, have been shown tohelp prevent the onset of undesirable conditions in man. Thesesubstances have been identified as either essential to human health(e.g. vitamins), or may, based on the increasing compilation of studies,play a role in maintaining health. For example, phytosterol and/orphytostanol esters have been shown to reduce serum cholesterol levels inman (mammals) upon consumption, and subsequent digestion in the gut. Themechanism for this is not completely known. Scientists theorize thatthese compounds block absorption of cholesterol produced and releasedfrom the body through the normal hepatic function, or consumed as acomponent of food. In reducing serum cholesterol levels, current wisdomdeduces that heart and circulatory health may be maintained bypreventing such conditions as arteriosclerosis, myocardial infarction,etc.

Nutritional ingredients, such as lutein, are currently available intablets or other dry forms because heretofore they could not besatisfactorily dispersed in water. The nutritional ingredients, such asthe phytosterols, phytostanols, lutein, isoflavones, Coenzyme Q₁₀, aretypically hydrophobic and are not ordinarily dispersible in aqueoussystems because they are only slightly water or oil soluble, if to anydegree at all.

The nutritional ingredients are desirable for use in beverages andcosmetics, in the form of aqueous suspensions, dispersions, orliposomes. Accordingly, a means for rendering these ingredients waterdispersible or dispersible in an aqueous system is needed and desired.

SUMMARY OF THE INVENTION

This invention relates to a stable suspension comprising a nutrient ornutritional ingredient. In particular, the nutrient is in an ester formand is associated with a dispersion aid and a dispersion agent.

DETAILED DESCRIPTION OF THE INVENTION

This invention involves a stable aqueous suspension which comprises anutrient or a nutritional compound or ingredient.

A suitable nutrient or nutritional ingredient is one which is suitablefor therapeutic treatment of an animal, e.g. a human being, byingestion, e.g. via a beverage, or by topical application, e.g. via alotion or cream, but which is unfortunately typically insoluble or onlyslightly soluble in water at room temperature, e.g. 20° C. to 25° C.,i.e. it is typically hydrophobic. It is these ingredients which are thesubject of this invention. Some suitable nutrients or nutritionalingredients include (1) a compound of the formula,

where R is OH, β-glucoside, 6″-O-acetylglucoside, or6″-O-malonylglucoside; R′ is H or OH; and R″ is H or OCH₃; such asisoflavone, e.g. a soybean derived isoflavone, and a substitutedisoflavone, such as daidzein, genistein and glycitein; (2) lutein, (3) aCoenzyme Q_(n), where n is an integer of 1-12, e.g. Coenzyme Q₁₀, (4) aphytosterol, e.g. a stigmasterol, sitbsterol, fucosterol,brassicasterol, campesterol, clionasterol, desmosterol, chalinosterol,poriferasterol, (5) a phytostanol, e.g. α or β sitostanol, campestanol,brassicastanol, clionastanol, stigmastanol, desmostanol, chalinostanol,poriferastanol, 22, 23 dihydrobrassicastanol, etc. and (6) a mixture ofany of the foregoing ingredients.

For purposes of the dispersions of this invention, which are intendedfor therapeutic use or as additives in association with a therapeutictreatment of animals, e.g. a human, a particular nutrient or mixture ofnutritional ingredients is present in the inventive aqueous dispersionsor suspensions in an effective nutritional amount, that is an amountwhich causes its desired nutritional or therapeutic effect.

The term “amount” as used herein refers to quantity or concentration asappropriate to the context. The amount of nutrient that constitutes anutritional amount varies according to factors such as potency of theparticular ingredient or mixture of ingredients, the mode ofadministration and the mechanical system used to administer thedispersion. A normally effective amount of a particular nutrient can beselected by those of ordinary skill in the art with due consideration ofsuch factors. Generally, a nutritionally effective amount will be from0.005 parts by weight to about 25 parts by weight based on 100 parts byweight of the dispersion or suspension.

A suitable aqueous system or medium is selected. A suitable aqueoussystem or medium for the dispersions or suspensions of this inventioninclude water and an aqueous solution of an organic alcohol of 1 to 6carbon atoms, e.g. ethanol, propylene glycol, glycerin, etc., and amixture of the foregoing; present in an amount of up to 10 percent (10%)by weight. The aqueous system is one which will permit a stabledispersion or suspension to be formed therein when combined with theselected nutrient or mixture of nutrients, which in turn is destined tobe in the form of at least a mono-ester associated with a suitabledispersion aid. The aqueous system is present in an amount which affordsthe desired dispersion and is dependent upon the selected nutrient ormixture of nutritional ingredients with the selected dispersion aid.Typically, the aqueous system comprises 55 to 95 weight percent of thedispersion or suspension.

The selected nutrient must first be converted to an ester, e.g. a mono-,di-, tri-ester, etc., if it does not already exist as at least amono-ester. Such conversion, if required, is conventionally carried out.In this regard, reference is made to such standard text as Briehler, andPearson, “Survey of Organic Synthesis”, Volumes 1 and 2, John Wiley &Sons.

Additionally, reference is made to Ingmar Westar et al., WO 09956558; M.P. van Amerongen et al., EP 00911385 A1 which describes the preparationof stanol, phytosterol and phytostanol esters.

A suitable dispersion aid is selected, i.e. an agent which when combinedor associated with the nutrient ester modifies such ester from itscrystalline form or morphous form to a dissolved form. The then modifiednutrient compound, i.e. ester, can then be further formulated ortreated, e.g. pulverized, particularized, homogenized, liquefied,dispersed in oil carrier, whereby it can be easily dispersed in water oran aqueous medium as a suspension.

A suitable dispersion aid includes (1) a triglyceride, such as sunfloweroil, soy bean oil, olive oil; a medium chain triglyceride i.e.triglycerides with mixed fatty acids of C₆ to C₁₂ lengths, such assn-glyceryl-1-caprylate, -2-caprate, -3-caprylate, etc., and a mixtureof any of the foregoing, (2) an essential oil extractive, such as orangeoil, lime oil, clove oil, oregano oil, peppermint oil, cinnamon oil,etc., and a mixture of the foregoing; (3) night primrose oil; (4) fishoils; (5) and a mixture of any of the foregoing aids.

The nutrient in ester form is combined or mixed with the dispersion aid,typically at a temperature ranging from 20 to 80° C., e.g. 70-75° C.,for 2 to 10 minutes to form the nutrient ester associated with thedispersion aid. By “associate” or “associated” means that the nutrientester has either reacted with the dispersion aid or has physicallyinteracted with the dispersion aid whereby it is either mixed therewith,encapsulated, wholly or partially, thereby, or becomes part of theinterstices thereof, solubilized or diluted.

A suitable dispersion agent is selected from (1) a lecithin, derivedfrom soybean or derived from egg which contain a complex mixture ofphospholipids consisting mainly of phosphatidylcholine,phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acidcombined with varying amounts of other substances such as triglycerides:the lecithin can be of standard grade or can be modified or refinedlecithin e.g. deoiled, hydrogenated, hydroxylated, enzyme modified,acetylated, etc.; (2) a hydrocolloid, e.g. xanthan gum, starch, pectin,gelatin, guar gum, carrageenan, methylcellulose, hydroxypropylcellulose; (3) a surfactant, e.g. cetylpyridinium chloride, polysorbate80, sorbitan monostearate, polyglycerol esters, block copolymers ofpropylene oxide, ethylene oxide; (4) a mixture of any of the forgoingdispersion agents.

An aqueous dispersion of the selected nutrient/aid combination utilizesthe dispersion agent in an amount effective to form and stabilize theresultant aqueous dispersion relative to an identical aqueousformulation not containing the dispersion agent, such that the activeingredient does not settle, cream or flocculate after agitation soquickly as to prevent reproducibility, e.g. reproducible dosing.Reproducible application, e.g. dosing, can be achieved if the resultantaqueous suspension is substantially uniform for minimally 1 to 2 hoursafter agitation thereof. The particular amount of dispersion agent thatconstitutes an effective amount is dependent upon the particulardispersion agent, the particular aqueous system or medium employed andthe particular nutritional ingredient/aid combination, or mixture ofingredients employed. It is therefore not practical to enumerate aspecific effective amount for use with specific dispersions orformulations of the invention, but such amount can readily be determinedby those of ordinary skill in the art with due consideration of thefactors set forth above. Generally, however, the dispersion agent can bepresent in a formulation in an amount from about 0.01 percent by weightto about 20 percent by weight, more preferably about 0.05 percent toabout 10 percent by weight, most preferably 0.5 percent to 5 percent byweight, based on the total weight of the dispersion or formulation.

Typically, the dispersion aid, e.g. sunflower oil, is combined with theactive ingredient or nutritional agent, e.g. phytosterol esters, at atemperature of 200 to 80° C. and is mixed for 2 to 10 minutes.Thereafter the combination is added to water containing dispersionagents, and is agitated thereto to form a mixture. The resultant mixtureis then subjected to a high shear treatment, using any commerciallyavailable equipment, e.g. Microfluidics M110, at a shear pressure of6500 to 24,000 psi, and preferably at a shear pressure of 7000 to 20,000psi, and most preferably at a shear 10,000 to 12,000 psi, whereby aparticle size of the active ingredient typically is less than 500 n,preferably less than 300 nm, preferably less than 250 nm, to form thedesired aqueous dispersion or suspension.

It is noted that the procedure described above can be modified, namelythe order of addition of the nutrient/aid combination, dispersion agent,and aqueous system to form the initial aqueous mixture, i.e. precedingto the described high shear treatment of the mixture.

The resultant aqueous nutrient dispersion can then be further formulatedand administered to a patient, e.g. a mammal such as a human being, byany conventional means, such as topically, orally; etc. Typically thedispersion or suspension is combined with other drugs, adjuvants, etc.in the form of a cream or lotion, e.g. a cosmetic, or in the form of aliquid, e.g. a beverage.

EXAMPLES Example 1

SELIN® brand phytosterol fatty acid esters from Cognis (6.0 g) wasdissolved in 24-0 g of NUSUN® oil, from Archer Daniels Midland, a higholeic acid sunflower oil, at 36° C. The resultant solution was added toan aqueous system comprising 78.5 percent by weight of deionized water(157 g), 4.0 percent by weight BLENDMAX K® lecithin from Central Soya (8g) and 2.5 percent polysorbate 80 (5 g). The resultant mixture wastreated two times with a Microfluidizer® M110T from Microfluidics at8,000 psi shear pressure to obtain a stable dispersion.

Example 2

The procedure of Example 1 was repeated using 15 g of SELIN®, 15 g ofNUNSUN® oil, 157 g of deionized water, 8 g of BLENDMAX K®, and 5 g ofpolysorbate 80 to obtain a stable dispersion.

Example 3

SELIN® (6 g) was combined with NUSUN® oil (24 g) and heated at 60° C.for 15 minutes to form a solution. Deionized water (155.8 g) andpolysorbate 80 (5 g) were mixed together and heated at 60° C. for 15minutes and then combined with the solution. BLENDMAX K® lecithin (8 g),citric acid (0.6 g) and potassium sorbate (0.6 g) were added to thecombined solution with mixing and then the resultant mixture was passedthrough a M110T Microfluidizer®, two times at a shear pressure of 8,000psi. A mean particle size of the stable dispersion of 178.3 nm wasobtained.

Example 4

The procedure of Example 3 was repeated with 10 g of SELIN®, 20 g ofNUSUN® oil, 155.8 g of deionized water, 8 g of BLENDMAX Ke®, 5 g ofpolysorbate 80, 0.6 g of citric acid and 0.6 g of potassium sorbate. Amean particle size of 194.6 nm of the stable dispersion was obtained.

Example 5

An experiment was conducted to see how high a percentage of thephytosterol esters could be incorporated into a stable dispersion. Thegeneral procedure was to combine BLENDMAX K®, Polysorbate 80, NUSUN® oiland SELIN® and mix these components thoroughly at a temperature of60°-65° C. To this mix was added deionized water, and the resultantmixture was mixed with a Silverson® high shear mixer. While fig, citricacid and potassium sorbate were added. Once the mixture became uniform,it was passed twice through a M110T Microfluidizer® at a shear pressureof 8,000 psi. The highest percentage of the SELIN in a stable dispersionobtained was 10.0 percent by weight, using the following weightpercentages of the ingredients.

Deionized Water 72.9 BLENDMAX ® 4.0 Polysorbate 80 2.5 NUSUN ® Oil 10.0SELIN ® 10.0 Citric acid 0.3 Potassium sorbate 0.3

Example 6

The procedure of Example 5 was repeated for lutein esters

A(g) B(g) Deionized Water 72.9 67.9 BLENDMAX ® 4.0 4.0 Polysorbate 802.5 2.5 NUSUN ® Oil 19.8 24.75 Citric acid 0.3 0.3 Potassium sorbate 0.30.3 Xangold ® Lutein esters 0.2 0.25Stable dispersions were obtained.

Example 7

7.5 g of Xangold®, a 15% lutein ester suspension in vegetable oil fromCognis, was dissolved with 17.5 g of orange oil at 65° C. 4.0 g ofBLENDMAX K®, 2.5 g of Polysorbate 80 were added and heated at 65° C. forseveral minutes. To the heated mixture was added 67.9 g of Deionizedwater, 0.3 g citric acid, and 0.3 g potassium sorbate while mixing witha Silverson® high shear mixer. The resultant mixture was then passedtwice through a M110 Microfluidizer® at a shear pressure of 10,000 psito yield a stable dispersion.

Example 8

The procedure of Example 7 was repeated using 3.75 g of Xangold® luteinesters and 21.25 g of olive oil instead of orange oil to obtain a stabledispersion.

1. An aqueous suspension of a hydrophobic nutrient which comprises, thenutrient in ester form associated with a dispersion aid selected fromthe group consisting of a triglyceride, an essential oil extractive,night primrose oil, fish oil, and a mixture of any of the foregoingdispersion aids; a dispersion agent; and an aqueous medium into whichsaid associated nutrient is suspended.
 2. The suspension as defined inclaim 1, wherein said associated nutrient is in a fully dispersed,uniform form in the aqueous medium.
 3. The suspension as defined inclaim 2, wherein the particles size of said fully dispersed, uniformform ranges from 50 to 400 nm.
 4. The suspension as defined in claim 1,wherein said ester is an ester of a nutritional compound selected fromthe group consisting of (a) a phytosterol selected from the groupconsisting of stigmasterol, sitosterol, facosterol, brassicasterol,campesterol, clionasterol, desmosterol, chalinosterol, poriferasterol,and any mixture of the foregoing phytosterols; (b) a phytostanol,selected from the group consisting of e.g. α sitostanol or β sitostanol,campestanol, brassicastanol, clionastanol, stigmastanol, desmostanol,chalinostanol, poriferastanol, 22, 23 dihydrobrassicastanol and any ofthe foregoing phytostanols; (c) lutein, (d) Coenzyme Q₁₀, (e)isoflavones, (f) and a mixture of any of the foregoing esters.
 5. Thesuspension as defined in claim 1, wherein said triglyceride is selectedfrom the group consisting of sunflower oil, soy bean oil, olive oil, amedium chain triglyceride, selected from the group containing fattyacids ranging from C₆ to C₁₂, and a mixture of any of the foregoingtriglycerides.
 6. The suspension as defined in claim 1, wherein saidessential oil extractive is one selected from the group consisting oforange oil, lime oil, clove oil, oregano oil, peppermint oil, cinnamonoil, and a mixture of any of the foregoing extractives.
 7. Thesuspension as defined in claim 1, wherein said dispersion agent isselected from the group consisting of (a) a lecithin, (b) ahydrocolloid, (c) a surfactant and (d) a mixture of any of the foregoingdispersion agents.
 8. The suspension as defined in claim 7, wherein saidlecithin is selected from the group consisting of lecithin derived fromsoybean and lecithin derived from egg.
 9. The suspension as defined inclaim 7, wherein said hydrocolloid is selected from a group consistingof xanthan gum, starch, pectin, gelatin, guar gum, carrageenan,methylcellulose, hydroxypropyl cellulose and a mixture of the foregoinghydrocolloids.
 10. The suspension as defined in claim 7, wherein saidsurfactant is selected from the group consisting of cetylpyridiniumchloride, polysorbate 80, sorbitan monostearate, a polyglycerol ester, ablock copolymer of propylene oxide, ethylene oxide and a mixture of anyof the foregoing surfactants.
 11. A method of rendering a hydrophobicnutritional compound water dispersible, which comprises: (a) treating anester form of the compound with a dispersion aid selected from the groupconsisting of a triglyceride, an essential oil extractive, nightprimrose oil, fish oil, and a mixture of any of the foregoing dispersionaids, to form a modified nutrient compound; (b) combining a dispersionagent with said modified nutrient compound in an aqueous medium to forman aqueous suspension; and treating said aqueous to a high shear forceto form a stable aqueous suspension.
 12. The method as defined in claim11, wherein said stable suspension has a mean particle size ranging from50 to 400 nm.
 13. The method as defined in claim 11, wherein said esteris an ester of a nutritional compound selected from the group consistingof (a) a phytosterol, selected from the group consisting ofstigmasterol, sitosterol, fucosterol, brassicasterol, campesterol,clionasterol, desmorsterol, chalinosterol, poriferasterol, and anymixture of the foregoing phytosterols; (b) a phytostanol selected fromthe group consisting of α sitostanol, β sitostanol, campestanol,brassicastanol, clionastanol, stigmastanol, desmostanol, chalinostanol,poriferastanol, 22, 23 dihydrobrassicastanol, and any mixture of theforegoing phytostanols; (c) lutein, (d) Coenzyme Q₁₀, (e) isoflavones,(f) and a mixture of any of the foregoing esters.
 14. The method asdefined in claim 11, wherein said triglyceride is selected from thegroup consisting of sunflower oil, soy bean oil, olive oil, a medium:chain triglyceride selected from the group containing fatty acidsranging from C₆ to C₁₂ and a mixture of any of the foregoingtriglycerides.
 15. The method as defined in claim 11, wherein saidessential oil extractive is one selected from the group consisting oforange oil, lime oil, clove oil, oregano oil, peppermint oil, cinnamonoil and a mixture of any of the foregoing extractives.
 16. The method asdefined in claim 11, wherein said dispersion agent is selected from thegroup consisting of (a) a lecithin, (b) a hydrocolloid, (c) a surfactantand (d) a mixture of any of the foregoing dispersion agents.
 17. Themethod as defined in claim 11, wherein said lecithin is selected fromthe group consisting of a lecithin derived from soybean and a lecithinderived from egg.
 18. The method as defined in claim 17, wherein saidhydrocolloid is selected from a group consisting of xanthan gum, starch,pectin, gelatin, guar gum, carrageenan, methylcellulose, hydroxypropylcellulose and a mixture of the foregoing hydrocolloids.
 19. The methodas defined in claim 17, wherein said surfactant is selected from thegroup consisting of cetylpyridinium chloride, polysorbate 80, sorbitanmonostearate, a polyglycerol ester, a block copolymer of propyleneoxide, ethylene oxide and a mixture of any of the foregoing surfactants.